Catalyst comprising indium salt and organic ionic liquid and process for friedel-crafts reactions

ABSTRACT

Disclosed is a catalyst composition based on an indium salt and an organic ionic liquid, a process for making the catalyst composition, and uses thereof. The catalyst composition is particularly suitable for Lewis acid catalysed electrophilic aromatic substitution reactions, such as Friedel-Crafts alkylation reactions an Friedel-Crafts acylation reactions.

The present invention relates to electrophilic aromatic substitutionreactions. In particular, the present invention is concerned with Lewisacid catalysed electrophilic aromatic substitution reactions, such asFriedel-Crafts alkylation reactions and Friedel-Crafts acylationreactions.

The present invention is particularly concerned with Lewis acidcatalysed electrophilic aromatic substitution reactions comprising theuse of an ionic liquid and an indium(III) halide. The ionic liquid andindium(III) halide components together form the “ionic liquid catalystsystem” of the present invention.

Friedel-Crafts reactions generally involve the alkylation or acylationof an aromatic compound by an electrophilic reagent. In a Friedel-Craftsalkylation reaction, a compound containing an aromatic ring, Ar isreacted with an alkylating agent in the presence of a Lewis acidcatalyst, typically AlCl₃ or BF₃, for example:

The alkylating agent is typically an alkyl halide, e.g. an alkylchloride. However, other alkylating agents, such as olefins, alcohols,dienes, alkynes, ethers sulfonates and inorganic ester can be used (seeRoberts, Khalaf: Friedel-Crafts Alkylation Chemistry, Marcel Dekker, NewYork, 1984 and Olah: Friedel-Crafts Chemistry, Wiley, New York, 1973).

In the Friedel-Crafts acylation reaction, an acylating agent is reactedwith an aromatic group, in the presence of a Lewis acid catalyst, suchas AlCl₃ to produce a ketone:

The acylating agent is typically an acyl halide, although acidanhydrides, carboxylic acids and ketenes can be used. The reaction canbe used for the acylating of a wide range of aromatic substrates.

The Friedel-Crafts acylation reaction is one of the most importantmethods for the preparation of aryl ketones and is thus a reaction ofconsiderable commercial and industrial importance.

However, there are several disadvantages associated with prior artFriedel-Crafts alkylation and acylation reactions. Typically, thereaction product is isolated by first quenching the reaction mixturewith water. This destroys the aluminium chloride catalyst, and at thesame time generates a large amount of aluminium-containing wasteproducts that must be disposed of. The catalyst thus cannot be re-usedor recycled.

Furthermore, in the Friedel-Crafts acylation process, the Lewis acid“catalyst” such as aluminium chloride or iron(III) chloride forms astable adduct with the reaction product (ketone), and this means thatthe catalyst must be used in stoichiometric quantities. Since thereaction product can only be liberated by hydrolyzing theketone-catalyst adduct, this leads to destruction of the Lewis-acid‘catalyst’. In other words, this process is not truly catalytic, nor isthe system recyclable.

Thus, there are significant environmental problems in the use ofaluminium. This in turn means that the Friedel-Crafts acylation andalkylation processes generate considerable amounts of waste, in terms ofaluminium salts and hydrochloric acid. Further, the hydrolysis processgenerates a large amount of aqueous solutions and suspensions containingaluminium salts, which, if used on an industrial scale, requiresadditional treatment steps for eventual disposal, and whichsignificantly adds to the cost of the operation.

WO 99/19288 discloses a Friedel-Crafts acylation reaction carried out inthe presence of an ionic liquid system as catalyst. The ionic liquidsystem employed therein comprises as a Lewis acid, iron(III) chloride,and as a base, an ionic liquid [Q]Cl, wherein Q can be a range oforganic cations such as substituted imidazolium, pyridinium, ammonium orphosphonium. The use of 1-ethyl-3-methylimidazolium chloride, [emim]Cl,is specifically disclosed.

According to WO 99/19288, iron(III) chloride and [emim]Cl, form theionic liquid system denoted “[emim]Cl—FeCl₃”. Friedel-Crafts acylationof benzene with acetyl chloride in the presence of this ionic liquidsystem produces acetophenone, which can be isolated by solventextraction. According to the disclosure of WO 99/19288, the catalyst isdeactivated in the process, and is not recovered. Further, it is statedthat the product acetophenone deactivates the catalyst so that it theproduct must be continuously removed from the reaction vessel to free upthe catalyst.

Therefore, it is desirable to develop Friedel-Crafts alkylation andacylation systems which are catalysed by species which can be used intruly catalytic amounts. Additionally, it is desirable to developFriedel-Crafts acylation catalysts that do not form stable adducts withthe ketone products, and thus allow the products of the reaction to beremoved from the reaction mixture without destruction of the catalystsystem, thus allowing the catalyst to be recycled.

It would be a further advantage to provide recyclable Friedel-Craftscatalyst systems that can be reused directly after isolation from thereaction mixture, i.e. with little or no additional purification steps.Furthermore, it is desirable that the recycled catalyst exhibits minimalloss of activity, that is, the recycled catalyst is not significantlydeactivated, so that subsequent reactions employing the recycledcatalyst proceeds with a percentage conversion of starting material(aromatic substrate) to product that is similar to the reaction withfresh catalyst (e.g. less than 25%, preferably less than 20% and evenmore preferably less than 15% loss of the initial percentageconversion).

Even more desirable would be a Friedel-Crafts catalyst system that canbe repeatedly recycled (e.g. more than two runs of recycled catalyst,preferably more than three runs of recycled catalyst, even morepreferably at least five runs of recycled catalyst). If would beparticularly advantageous to provide such Friedel-Crafts catalystsystems that can be repeated recycled with minimal loss of catalystactivity.

The present invention provides a catalyst system and Friedel-Craftsprocesses that overcomes one or more of the problems associated withprior art Friedel-Crafts systems.

According to a first aspect of the present invention, there is provideda catalyst composition formed by combining an organic ionic liquid withan indium(III) halide.

The catalyst composition of the present invention thus comprises inadmixture (a) an organic ionic liquid and (b) an indium(III) halide.Although the actual identity of the catalytic species is not known withcertainty, it is believed that the catalyst composition comprises ionicspecies resulting from reaction between the organic ionic liquid andindium chloride.

The catalyst composition of the present invention may thus be describedas comprising a plurality of ionic species including:

(a) cationic species derived from an organic ionic liquid, and

(b) at least one species comprising indium,

and may additionally comprise halide ions.

According to an alternative definition of the present invention, thecatalyst composition comprises a plurality of ionic species and beingobtainable by mixing an organic ionic liquid and an indium(III)(preferably an indium(III) halide, and more preferably, indium(III)chloride).

The term “ionic liquid” refers to a liquid that is capable of beingproduced by melting a solid, and when so produced, consists solely ofions. Ionic liquids may be derived from organic salts, especially saltsof heterocyclic nitrogen-containing compounds, and such ionic liquidsare particularly preferred for use in the processes of the presentinvention. Ionic liquids may be regarded as consisting of twocomponents, which are a positively charged cation and a negativelycharged anion.

An ionic liquid may be formed from a homogeneous substance comprisingone species of cation and one species of anion, or can be composed ofmore than one species of cation and/or anion. Thus, an ionic liquid maybe composed of more than one species of cation and one species of anion.An ionic liquid may further be composed of one species of cation, andone or more species of anion.

Thus, in summary, the term “ionic liquid” as used herein may refer to ahomogeneous composition consisting of a single salt (one cationicspecies and one anionic species) or it may refer to a heterogeneouscomposition containing more than one species of cation and/or more thanone species of anion. For the purposes of the present invention, it ispreferred that the anion species of the ionic liquid comprises a halide,i.e. F⁻, Cl⁻, Br⁻ or I⁻. Preferably, the ionic liquid employed in thepresent invention is composed of a single species of halide anions, withCl⁻ being particularly preferred.

The term “ionic liquid” includes compounds having both high meltingtemperature and compounds having low melting points, e.g. at or belowroom temperature (i.e. 15-30° C.). The latter are often referred to as“room temperature ionic liquids” and are often derived from organicsalts having pyridinium and imidazolium-based cations.

A feature of ionic liquids is that they have particularly low(essentially zero) vapour pressures. Many organic ionic liquids have lowmelting points (e.g. less than 100° C., particularly less than 100° C.,and around room temperature, e.g. 15-30° C. and some have melting pointswell below 0° C. For the purposes of the present invention, it isdesirable that the organic ionic liquid has a melting point of 250° C.or less, preferably 150° C. or less, more preferably 100° C. or less andeven more preferably 80° C. or less, although any compound that meetsthe criteria of being a salt (consisting of an anion and cation) andwhich is liquid at or near the reaction temperature, or exists in afluid state during any stage of the reaction can be defined as anorganic ionic liquid especially suitable for use in the process of thepresent invention.

Ionic liquids useful for preparing the catalyst composition of thepresent invention include those comprising an imidazolium, pyridinium,pyridazinium, pyrazinium, oxazolium, triazolium, pyrazolium,pyrrolidinium, piperidinium, tetraalkylammonium or tetraalkylphosphoniumsalt.

Ionic liquids for use in the present invention include salts (preferablyhalide salts, and especially chloride salts) of imidazoles, pyridines,pyridazines, pyrazines, oxazoles, triazoles or pyrazoles. Preferredionic liquids for use in the present invention are imidazolium,pyridinium, pyridazinium, pyrazinium, oxazolium, triazolium orpyrazolium halide salts.

Especially preferred ionic liquids are halide salts of an alkylated orpolyalkylated compound of pyridine, pyridazine, pyrimidine, pyrazine,imidazole, pyrazole, oxazole or triazole.

Also preferred ionic liquids for use in the present invention are thosecomprising an imidazolium, pyridinium, pyridazinium, pyrazinium,oxazolium, triazolium, pyrazolium, pyrrolidinium or piperidinium halidesalt, with imidazolium halide salts (particularly chloride) beingparticularly preferred.

Thus, ionic liquids suitable for use in the present invention includethose selected from a compound of formula:

wherein

-   -   each R^(a) is independently selected from a C₁ to C₄₀ linear or        branched alkyl or a C₃ to C₈ cycloalkyl group, wherein said        alkyl or cycloalkyl group which may be substituted by one to        three groups selected from: C₁ to C₆ alkoxy, C₆ to C₁₀ aryl, C₁        to C₃₀ aralkyl and C₁ to C₃₀ alkaryl;    -   each R^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) can be        the same or different and are each independently selected from H        or any of the R^(a) groups as defined above; and    -   [A]⁻ represents a monovalent anion (halide is preferred, and        chloride is especially preferred).

Also preferred are ionic liquids selected from a compound of formula:

wherein R^(a)-R^(h) and [A]⁻ are as defined above.

Also preferred are ionic liquids selected from a compound of formula:

wherein R^(a)-R^(h) and [A]⁻ are as defined above.

Also preferred are ionic liquids selected from a compound of formula:

wherein [A]⁻, R^(a), R^(b), R^(c), R^(d), R^(e) and R^(g) are as definedabove.

Imidazole-based ionic liquids selected from a compound of formula:

wherein R^(a), R^(g) and [A]⁻ are as defined above are especiallyuseful.

In the above formulae, it is preferred that each R^(a) represents C₁ toC₄₀ (preferably C₁ to C₂₀, even more preferably C₁ to C₈) linear orbranched alkyl.

Also, in the above formulae, it is preferred that each R^(g) and R^(h)represents C₁ to C₄₀ (preferably C₁ to C₂₀, more preferably C₁ to C₈)linear or branched alkyl.

Particularly preferred are ionic liquids of the above formulae whereinR^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) each representshydrogen.

A further preferred group of ionic liquids are those having the aboveformulae wherein R^(a), R^(g) and R^(h) each represents a C₁-C₂₀ alkylgroup.

The anion [A]⁻ in the ionic liquids of the above formulae is preferablyhalide, i.e. F⁻, Cl⁻, Br⁻ or I⁻. Cl⁻ or Br⁻ are preferred halide anions,and Cl⁻ is especially preferred.

Specific examples of suitable ionic liquids for the catalystcompositions of the present invention include:

1-butyl-3-methylimidazolium halide

1-octyl-3-methylimidazolium halide

1-decyl-3-methylimidazolium halide

1-dodecyl-3-methylimidazolium halide

1-ethyl-3-methylimidazolium halide

1-hexyl-3-methylimidazolium halide

1-hexylpyridinium halide

1-octylpyridinium halide

In the above examples of suitable ionic liquids, it is preferred thatthe halide anion is chloride.

Good results have been obtained when 1-ethyl-3-methylimidazoliumchloride or 1-butyl-3-methylimidazolium chloride are employed asstarting materials for the catalyst compositions of the presentinvention.

With regards to the indium salt starting material of the catalystcomposition of the present invention, indium(III) halides (i.e. InF₃,InCl₃, InBr₃ and InI₃). However, indium(III) chloride and indium(III)bromide are preferred, and indium(III) chloride is especially preferred.

The amount of free indium(III) chloride used to form the catalystcomposition of the present invention is typically in the ratio of 1 mole% to 100 mole % (preferably 1 mole % to 50 mole %, more preferably 1mole % to 30 mole %, even more preferably 1 mole % to 10 mole %) of thestarting materials (e.g. organic ionic liquid). Good results have beenobtained using amount ranges of 2 mole % to 7 mole % and 3 mole % to 6mole %.

Typical ratio ranges of indium(III) chloride to organic ionic liquidvary from 4:1 to 1:1. Preferably the indium(III) chloride to organicionic liquid ratio is from 3:1 to 2.5:1, and even more preferably, theratio is 2:1 to 2.5 to 1. Good results have been obtained at anindium(III) chloride to organic ionic liquid ratio of 2:1.

According to a second aspect of the present invention, there is provideda process for the production of a catalyst composition as defined above,said process comprising admixing an organic ionic liquid as definedabove with an indium(III) salt (preferably an indium(III) halide, evenmore preferably indium(III) chloride).

Preferably, the admixing is conducted at or beyond the melting point ofthe organic ionic liquid, typically at a temperature range of 25° C. to200° C. (preferably 50° C. to 150° C., even more preferably 60° C. to100° C.).

The catalyst composition of the present invention is preferably misciblewith water. This has the advantage that the catalyst can be isolatedafter use by extraction with water.

Thus, for example, a catalyst composition for use in the process of thepresent invention can be formed from indium(III) chloride in conjunctionwith room temperature ionic liquid systems (RTILS) based e.g. on the1,3-dialkylimidazolium ring system (or any other suitable organiccationic species) to yield a Lewis-acid catalyst system (“chloroindatemelt”), which can be recovered from the alkylation/acylation reactionmixture by extraction with water and which, upon removal of water,yields the indium(III) chloride catalyst system, which may be recycled.

According to a third aspect of the present invention, there is provideda process for the Lewis acid catalysed electrophilic substitution of anaromatic substrate comprising the use of the catalyst compositionaccording to the present invention.

Thus, the catalyst of the present invention is particularly effective inLewis acid catalysed electrophilic substitution reactions (e.g.Friedel-Crafts alkylation and Friedel-Crafts acylation).

In accordance with the present invention, there is provided a processfor the Friedel-Crafts alkylation or Friedel-Crafts acylation of anaromatic substrate comprising mixing the catalyst composition with anaromatic substrate and an alkylation or acylating agent.

It will be appreciated that these steps can be carried out in anysuitable order. Preferably, the aromatic substrate is added to thecatalyst composition, and the alkylating or acylating agent addedsubsequently, or the catalyst is added to the aromatic substratefollowed by addition of the alkylating or acylating agent.

It is preferred that the catalyst composition is melted before thearomatic substrate is added.

After mixing the melted catalyst composition, the alkylating oracylating agent is added and the alkylation or acylation reaction isallowed to take place. The reaction temperature will depend on thenature of the substrate. However, typical temperature ranges for thealkylation and acylation reactions are 25° C. to 200° C., preferably 50°C. to 150° C. and more preferably 70° C. to 90° C.

After reaction, the alkylated or acylated aromatic product is isolatedthe reaction mixture by optionally adding a water-immiscible organicsolvent to the reaction mixture to form an organic solution containingthe product; and adding water to the reaction mixture in order todissolve the catalyst composition. The immiscible solutions can then beseparated into two components, namely the aqueous extracts containingthe catalyst composition and the product or organic solution containingthe product. The immiscible organic solvent can be removed from theproduct by distillation. The catalyst composition can be recovered bydistillation/evaporation.

Any suitable water-immiscible solvent can be used to dissolve alkylatedor acylated aromatic product. Typically used solvents include hexanes,diethyl ether, benzene, toluene and dichloromethane.

The alkylation and acylation processes of the present invention offerssignificant advantages compared to prior art processes because thecatalyst can be recycled for subsequent reuse. Also the alkylation andacylation reactions can be conducted without the need for an additionalreaction solvent (typically in Friedel-Crafts acylation reactions,nitrobenzene is employed as the reaction solvent). This reduces theamount of organic waste requiring disposal.

According to a fourth aspect of the present invention there is provideda process for the Friedel-Crafts alkylation of an aromatic substratecomprising reacting the aromatic substrate with an alkylation agent, inthe presence of a catalyst composition as defined herein, to form analkyl-substituted aromatic compound

The alkylating agent is typically an alkyl halide, olefin or alcohol.Alternatively the alkylating agent is an alkyl halide substituent, anolefin substituent or an alcohol substituent, said substituent beingattached to a ring carbon atom of the aromatic substrate such that thereaction results in an intramolecular alkylation reaction to form afused ring, e.g:

The alkylating agent typically comprises a linear or branched C₁ to C₂₀alkyl halide; a linear or branched C₂ to C₂₀ olefin; or a linear orbranched C₁ to C₂₀ alcohol; or a C₃ or C₅ alkyl halide substituent, a C₄to C₅ olefin substituent or a C₃ to C₅ alcohol substituent, saidsubstituent being attached to a ring carbon atom of the aromaticsubstrate such that the reaction results in an intramolecular alkylationreaction to form a fused ring.

Preferred alkylating agents are selected from a C₁ to C₂₀ alkyl halideor a C₃ to C₅ alkyl halide substituent, said substituent being attachedto a ring carbon atom of the aromatic substrate such that the reactionresults in an intramolecular alkylation reaction to form a fused ring.

Compounds containing an alkyl chloride or alkyl bromide group areespecially preferred. Even more preferred are alkyl chloride alkylatingagents.

According to a fifth aspect of the present invention there is provided aprocess for the Friedel-Crafts acylation of an aromatic substratecomprising reacting the aromatic substrate with an acylation agent, inthe presence of a catalyst composition as defined herein, to form anaromatic ketone.

Any suitable acylating agent can be used. Preferably, the acylatingagent is selected from: a cyclic aliphatic acid halide, a linear orbranched aliphatic acid halide or an aromatic acid halide; a carboxylicacid; or a carboxylic acid anhydride. The acylating agent may alsocomprise a linear aliphatic acid halide substituent, a carboxylic acidsubstituent, or an acid anhydride substituent, said substituent beingattached to a ring carbon atom of the aromatic substrate such that thereaction results in an intramolecular acylation reaction to form a fusedring, e.g.:

Also preferred are acylating agents comprising a C₄ to C₁₀ cyclicaliphatic acid halide, a C₂ to C₂₀ linear or branched aliphatic acidhalide or a C₇ to C₂₀ aromatic acid halide; a C₂ to C₂₀ carboxylic acid;and a C₄ to C₂₀ acid anhydride; or the acylating agent is a C₃ to C₅linear aliphatic acid halide substituent or a C₃ to C₅ carboxylic acidsubstituent said substituent being attached to a ring carbon atom of thearomatic substrate such that the reaction is an intramolecular acylationreaction to form a fused ring.

Especially preferred are acylating agents comprising a C₂ to C₂₀ linearor branched aliphatic acid halide; or a C₃ to C₅ linear aliphatic acidhalide substituent said substituent being attached to a ring carbon atomof the aromatic substrate such that the reaction is an intramolecularacylation to form a fused ring.

Particularly preferred acylating agents include acid halides or theacylating agent can be an acid halide substituent present on thearomatic substrate. Acid chlorides or acid chloride substituents areespecially preferred.

For example, acylating agents useful in the process of the presentinvention include compounds of the general formulaeR¹COX   (I)andR¹CO(O)COR²   (II),wherein each R¹ and R² , which may be the same or different, representsa substituted or unsubstituted aliphatic, aromatic or heterocyclic groupcontaining from 1 to 40, preferably 1 to 25 or 1 to 10, and mostpreferably 1 to 8 carbon atoms, and X represents a leaving group, suchas halide (preferably chloride or bromide).

Thus, for example, each of R¹ and R² may be the same or different andeach is independently selected from:

C₁ to C₄₀ straight chain or branched alkyl which may be substituted byone to three groups selected from: C₁ to C₆ alkoxy, C₆ to C₁₀ aryl, NO₂,C₁ to C₃₀ aralkyl and C₁ to C₃₀ alkaryl; and

C₃ to C₈ cycloalkyl wherein said alkyl or cycloalkyl group may besubstituted with 1-3 substituents independently selected from: C₁ to C₁₀alkyl, C₃ to C₈ cycloalkyl, or OR³ wherein R³ is selected from C₁ to C₂₀alkyl.

Specific examples of acylating agents include: acetic anhydride,propanoic anhydride, isobutyric anhydride, trifluoroacetic anhydride,monochloroacetyl anhydride, dichloroacetyl anhydride, acetyl chloride,monochloroacetyl chloride, dichloroacetyl chloride, propanoyl chloride,isobutanoyl chloride, pivaloyl chloride, and crotonyl chloride.Particularly useful are acylating agents include acetic anhydride,propanoic anhydride, isobutyric anhydride, acetyl chloride, propanoylchloride and butanoyl chloride.

The present process has been successfully employed for e.g. theFriedel-Crafts acylation of an aromatic substrate with an acylationagent to form a ketone, wherein a system of indium (III) chloride and a1,3-dialkylated imidazolium chloride or other organic anionic species isused.

Thus, the present invention includes a homogeneous process for theFriedel-Crafts acylation of various aromatic substrates, which comprisesusing a combination of indium(III) chloride and a 1,3-dialkylatedimidazolium chloride or other organic cationic species, whereby theamount of free indium(III) chloride used is in the ratio of 1 mole % to100 mole % of the starting materials, and where the product can beremoved easily from the reaction mixture by a simple extraction of thecatalyst system from the reaction mixture with water, and wherein theindium based catalyst system can be regenerated by subsequent removal ofwater from the aqueous wash, and wherein the recovered indium basedcatalyst system may be re-employed in the conversion of fresh startingmaterials with no significant large loss in conversion of startingmaterials to products.

It will be noted that the alkylation and acylation processes employingthe catalyst of the present invention are of general applicability to awide range of substrates and wide range of alkylation/acylationreagents. These include substrates that comprise at least one aromaticgroup. The aromatic group may be substituted with various substituents.Providing that these substituents are stable under the Friedel-Craftsreaction conditions, or have been suitably protected (see e.g. Greene,T. W. Protective Groups in Organic Synthesis, Wiley, New York, 1981),the present processes may be used successfully on such substrates.

Typical starting materials for the acylation reaction include one ormore of the following: toluene, anisole, benzoic anhydride, benzoylchloride, acetic anhydride and acetyl chloride.

As indicated above, in the alkylation and acylation process of thepresent invention, the product may be removed from the reaction mixtureby a simple extraction of the catalyst system from the reaction mixturewith water. The product can be removed as a liquid (e.g. by decantation)or solid (e.g. by decantation, filtration, etc.) directly from thereaction mixture or can be dissolved in a water-immiscible organicsolvent and separated from the catalyst component of the reactionmixture by extraction. The organic solvent containing dissolved productcan be removed by distillation.

Advantageously, the indium based catalyst system can be separated fromthe reaction mixture as an aqueous solution. The catalyst can then beregenerated by subsequent removal of water from the aqueous phase. Also,it has been surprisingly found that it is possible to reuse theregenerated catalyst directly after removal of the water without theneed for any further purification steps, although if necessary furtherpurification steps may be carried out in order to optimize the catalystpurity/efficiency.

Unless otherwise indicated, the terms used herein have the followingmeanings:

“Alkyl” (including alkyl portions of alkyoxy, alkaryl, aralkyl,alkylamino, dialkylamino) represents straight and branched carbon chainscontaining from 1 to 40 carbon atoms, preferably 1 to 20 carbon atomsand more preferably 1 to 8 carbon atoms.

“Cycloalkyl” represents saturated carbocyclic rings branched orunbranched containing from 3 to 20 carbon atoms, preferably 3 to 8carbon atoms. Such cycloalkyl groups include cyclopentyl and cyclohexyl.

“Heterocycloalkyl” represents a saturated, branched or unbranchedcarbocyclic ring containing from 3 to 12 carbon atoms, preferably from 4to 6 carbon atoms, wherein the carbocyclic ring is interrupted by 1 to 3heteroatom moieties selected from —O—, or —N(C₁ to C₆ alkyl), or NH.Such heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2-, 3-or 4-piperidinyl, 2-, 3- or 4-piperizinyl, morpholinyl, 2- or3-pyrrolidinyl and 2- or 4-dioxanyl.

“Aryl” including aryl moieties in e.g. aralkyl represents a carbocyclicgroup containing from 6 to 15 carbon atoms (preferably from 6 to 10carbon atoms) and having at least one aromatic ring, with all availablesubstitutable carbon atoms of the carbocyclic group being intended aspossible points of attachment. Preferred aryl groups include phenyl andnaphthyl.

“Heteroaryl” represents cyclic groups having at least one heteroatomselected from —O— or —N—, said heteroatom interrupting a carbocyclicring structure and having a sufficient number of delocalised pielectrons to provide aromatic character, with the aromatic heterocyclicgroups preferably containing from 2 to 14 carbon atoms. Suitableheteroaryl groups include pyridine, indole, imidazole, pyridazine,pyrazine, oxazole, triazole, pyrazole, and purines and pyrimidines.

The basic reaction involved in the acylation process of the invention isshown in the following equation:

wherein R and R′ can represent any suitable substituent. Examples ofsuitable aromatic substrates include toluene and anisole. Examples ofsuitable acylating agents include benzoic anhydride, benzoyl chloride,acetic anhydride and acetyl chloride, all of which are all readilyavailable.

The starting materials for the catalyst composition e.g. indium(III)halides and ethylmethylimidazolium chloride and butylmethylimidazoliumchloride are also readily available.

In an illustrative practical operation of the acylation reaction of thepresent invention, indium(III) chloride and the 1,3-dialkylimidazoliumsystem (e.g. 1,3-dialkylimidazolium chloride) are stirred together at80° C. until a melt is formed. This melt is the catalyst composition ofthe present invention. The nature of the reaction taking place betweenthe organic ionic liquid, 1,3-dialkylimidazolium chloride andindium(III) chloride is uncertain. However, it is believed that thecomposition may contain [bmim]⁺ In₂Cl₇ ⁻. Other ionic species {including[bmim]⁺ In_(x)Cl_(y) ⁻ wherein x and y are integers from 1 to 10) mayalso be present in the composition.

The aromatic substrate (e.g. anisole or toluene) is added, followed bythe acylating agent (such as acetic anhydride or benzoic anhydride).

The mixture is then stirred at a temperature of 80° C., for a period oftime (typically 2 hours), after which time the reaction mixture isremoved from the source of heat. A water-immiscible solvent may then beadded. This solvent may be unrelated to the starting materials of thereaction, or it may be related (e.g. the water-immiscible solvent may bethe same as the aromatic substrate—i.e. excess starting material such asanisole or toluene may be added at this stage, since they arewater-immiscible

The indium based catalyst system of the present invention may then beremoved from the reaction by washing the solvent solution with water.

The aqueous solution can then be dehydrated in vacuo to remove water,followed by drying (e.g. in vacuo), to yield the recycled indium basedcatalyst system, which may then be re-employed as a catalyst with freshstarting materials.

The desired product of the acylation reaction (the ketone) may beliberated from the solvent solution by washing this with either hotwater, or with aqueous sodium hydroxide solution to remove the benzoicacid (produced in benzoylation reactions using benzoic anhydride) andany excess acylating agent (such as acetyl chloride or benzoicanhydride).

Finally, distillation of the resulting mixture yields unreacted aromaticsubstrate which can be fed back into the process, and the ketoneproduct.

The processes of the present invention may be conducted as a batchprocess or advantageously, as a continuous process.

Selectivity

The selectivity achieved using the acylation process of the presentinvention to benzoylate anisole has been found to be the same obtainedfor any other processes were used for comparison (an para:ortho isomerratio of ca. 94% was achieved).

Recyclability

In the benzoylation of anisole with benzoic anhydride, the amount offree indium(III) chloride used (as a component of the chloroindate melt)was 5 mole % of the anisole used in the reaction.

The reaction was carried out at 80° C. for two hours in every case.Diethyl ether was used as the water-immiscible solvent, and the indiumbased catalyst system was removed from the reaction mixture by aqueouswashing followed by dehydration. The chloroindate melt thus obtained wasre-used in the conversion of fresh starting materials to products. Theprocess was repeated until 6 runs had been carried out.

Conversion of starting materials based on anisole started at 79% andsurprisingly remained at 62% after the sixth run.

In all cases, the isomer selectivity remained at ca. 94%.

The present invention will be illustrated further by way of thefollowing examples and figures:

FIG. 1 is a schematic diagram showing the process steps for theacylation of anisole with benzoic anhydride using a catalyst compositionof the present invention.

EXAMPLE 1

1-Butyl-3-methylimidazolium chloride (1.0 g) (5.65 mmol) was added toindium(III) chloride (2.5 g) (11.3 mmol) and stirred together at 80° C.until the mixture formed an opaque white liquid (10 min).

Anisole (10 ml, 9.95 g, 91.9 mmol) was added, and the mixture stirredfor 5 min. Benzoic anhydride (23 g, 101.7 mmol, 1.1 equivalents based onanisole) was then added to the reaction mixture, and the mixture stirredunder a closed atmosphere at 80° C. for 2 hr.

The yield of 4-methoxybenzophenone based on anisole was 79.9% (HPLC).

The reaction mixture was then removed from the source of heat, and whenit had cooled to ambient temperature, diethyl ether (100 ml) was added,and the mixture shaken until everything had dissolved to form ahomogenous solution.

This solution was then shaken with water (3×30 ml), and the aqueousextracts were combined, and then concentrated in vacuo. Finally, theresidue was heated to ca. 100° C. under vacuum to remove residual waterwhereupon it resembled in appearance the opaque white liquid previouslydescribed.

This liquid was then taken and re-used as a catalyst for the conversionof fresh anisole and benzoic anhydride as described above.

The ether extract was washed with 2M sodium hydroxide (solution) (2×70ml) yielding and finally water (50 ml), and the solvents removed invacuo to yield the product, a mixture of 2-methoxybenzophenone and4-methoxybenzophenone.

The process is further illustrated in FIG. 1. In FIG. 1, anisole andbenzoic anhydride are fed into a batch reactor containing thechloroindate melt. The mixture is stirred at 80° C. for several hours.

The reaction mixture is run into a separation chamber. Here organicsolvent is added (unnecessary if the reaction was run anisole rich—i.e.a large excess of anisole is employed). The chloroindate melt isextracted by washing repeatedly with water.

The chloroindate melt solution is evaporated to dryness, and is fed backinto step 1.

Benzoic acid and benzoic anhydride are removed by washing with NaOH (orhot water) leaving 4-methoxybenzophenone.

Distillation yields the product, as well as anisole, which can bere-used in Step 1.

EXAMPLE 2

1-Butyl-3-methylimidazolium chloride (1.0 g) (5.65 mmol) was added toindium(III) chloride (2.5 g) (11.3 mmol) and stirred together at 80° C.until the mixture formed an opaque white liquid (10 min).

Toluene (0.6 ml, 0.52 g, 5.67 mmol) was added followed by benzoicanhydride (1.4 g, 6.19 mmol, 1.1 equivalents with respect to toluene).

The mixture was stirred at 100° C. and left to stir overnight. HPLCanalysis indicated that the reaction had gone to completion.

Diethyl ether (20 ml) was added, and the mixture washed with water (3×20ml).

The aqueous extracts were combined and dried as previously described toyield chloroindate melt which was re-used in conversion of startingmaterials under the same conditions.

Again, full conversion of the starting materials was observed.

1. A catalyst composition formed by combining an organic ionic liquidwith an indium(III) halide.
 2. A catalyst composition comprising inadmixture (a) an organic ionic liquid and (b) an indium(III) halide. 3.A catalyst composition according to claim 1 where the catalystcomposition comprises ionic species resulting from reaction between theorganic ionic liquid and indium chloride.
 4. A catalyst compositioncomprising a plurality of ionic species including: (a) cationic speciesderived from an organic ionic liquid, and (b) at least one speciescomprising indium.
 5. A catalyst composition according to claim 4further comprising a halide ion.
 6. A catalyst composition according toclaim 4 comprising a plurality of ionic species and being obtainable bymixing an organic ionic liquid and an indium(III) salt.
 7. A catalystcomposition according to claim 4 wherein the indium(III) salt is anindium(III) halide.
 8. (canceled)
 9. (canceled)
 10. A catalystcomposition according to claim 1 wherein the ionic liquid is a halidesalt of an alkylated or polyalkylated compound of pyridine, pyridazine,pyrimidine, pyrazine, imidazole, pyrazole, oxazole or triazole.
 11. Acatalyst composition according to claim 1 wherein the ionic liquidcomprises an imidazolium, pyridinium, pyridazinium, pyrazinium,oxazolium, triazolium, pyrazolium, pyrrolidinium, piperidinium,tetraalkylammonium or tetraalkylphosphonium salt.
 12. A catalystcomposition according to claim 1 wherein the ionic liquid comprises animidazolium, pyridinium, pyridazinium, pyrazinium, oxazolium,triazolium, pyrazolium, pyrrolidinium or piperidinium halide salt. 13.(canceled)
 14. A catalyst composition according to claim 1 wherein theionic liquid is selected from a compound of formula:

wherein each R^(a) is independently selected from a C₁ to C₄₀ linear orbranched alkyl or a C₃ to C₈ cycloalkyl group, wherein said alkyl orcycloalkyl group which may be substituted by one to three groupsselected from: C₁ to C₆ alkoxy, C₆ to C₁₀ aryl, C₁ to C₃₀ aralkyl and C₁to C₃₀ alkaryl; each R^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h)can be the same or different and are each independently selected from Hor any of the R^(a) groups as defined above; and [A]⁻ represents ahalide anion.
 15. (canceled)
 16. (canceled)
 17. A catalyst compositionaccording to claim 1 wherein the ionic liquid is selected from acompound of formula:

wherein each R^(a) is independently selected from a C₁ to C₄₀ linear orbranched alkyl or a C₃ to C₈ cycloalkyl group, wherein said alkyl orcycloalkyl group which may be substituted by one to three groupsselected from: C₁ to C₆ alkoxy, C₆ to C₁₀ aryl, C₁ to C₃₀ aralkyl and C₁to C₃₀ alkaryl; each R^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h)can be the same or different and are each independently selected from Hor any of the R^(a) groups as defined above; and [A]⁻ represents ahalide anion.
 18. A catalyst composition according to claim 1 whereinthe ionic liquid is selected from a compound of formula:

wherein R^(a), R^(g) and [A]⁻ are as defined in claim
 7. 19. A catalystcomposition according to claim 14 wherein each R^(a) represents C₁ toC₄₀ linear or branched alkyl.
 20. A catalyst composition according toclaim 14 wherein each R^(g) and R^(h) represents C₁ to C₄₀ linear orbranched alkyl.
 21. A catalyst composition according to claim 14 whereinR^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) each representshydrogen.
 22. (canceled)
 23. A catalyst composition according to claim14 wherein [A]⁻ represents Cl⁻ or Br⁻.
 24. (canceled)
 25. A catalystcomposition according to claim 14 wherein the ionic liquid is selectedfrom 1,3-ethylmethylimidazolium chloride or 1,3-butylmethylimidazoliumchloride.
 26. A catalyst composition according to claim 7 wherein theindium(III) halide is indium(III) chloride.
 27. A process for theproduction of a catalyst composition according to claim 1, said processcomprising admixing an organic ionic liquid as defined in any precedingclaim with an indium(III) halide.
 28. (canceled)
 29. A process for theLewis acid catalysed electrophilic substitution of an aromatic substratecomprising the use, as a catalyst, of a composition according toclaim
 1. 30. A process according to claim 29 wherein the Lewis acidcatalysed electrophilic substitution reaction is a Friedel-Craftsalkylation reaction to form an alkyl substituted aromatic compound, orFriedel-Crafts acylation reaction to form an aromatic ketone.
 31. Aprocess according to claim 29 comprising admixing a catalyst compositionformed by combining an organic ionic liquid with an indium(III) halide,with an aromatic substrate and an alkylating or acylating agent. 32.(canceled)
 33. (canceled)
 34. A process according to claim 29 whereinthe product is isolated from the reaction mixture by a procedurecomprising the steps of: (i) optionally adding a water-immiscibleorganic solvent to form an organic solution containing the product; and(ii) adding water to the reaction mixture to dissolve the catalystcomposition and separating the aqueous extracts containing the catalystcomposition from the product or from the organic solution containing theproduct; and (iii) removing any solvent from the product.
 35. A processaccording to claim 29 further comprising recycling the catalyst forsubsequent use.
 36. A process according to claim 29 wherein the catalystis isolated by evaporation of water.
 37. (canceled)
 38. A processaccording to claim 31 wherein the alkylating agent is an alkyl halide,olefin or alcohol; or wherein the alkylating agent is an alkyl halidesubstituent, an olefin substituent or an alcohol substituent, saidsubstituent being attached to a ring carbon atom of the aromaticsubstrate such that the reaction results in an intramolecular alkylationreaction to form a fused ring.
 39. A process according to claim 31wherein the alkylating agent is a linear or branched C₁ to C₂₀ alkylhalide; a linear or branched C₂ to C₂₀ olefin; or a linear or branchedC₁ to C₂₀ alcohol; or a C₃ or C₅ alkyl halide substituent, a C₄ to C₅olefin substituent or a C₃ to C₅ alcohol substituent, said substituentbeing attached to a ring carbon atom of the aromatic substrate such thatthe reaction results in an intramolecular alkylation reaction to form afused ring.
 40. A process according to claim 31 wherein the alkylatingagent is a C₁ to C₂₀ alkyl halide or a C₃ to C₅ alkyl halidesubstituent, said substituent being attached to a ring carbon atom ofthe aromatic substrate such that the reaction results in anintramolecular alkylation reaction to form a fused ring.
 41. A processaccording to claim 38 wherein the alkyl halide or alkyl chloridesubstituent is an alkyl chloride or alkyl bromide.
 42. (canceled)
 43. Aprocess according to claim 31 wherein the acylating agent is selectedfrom: a cyclic aliphatic acid halide, a linear or branched aliphaticacid halide or an aromatic acid halide; a carboxylic acid; or acarboxylic acid anhydride; or wherein the acylating agent is a linearaliphatic acid halide substituent, a carboxylic acid substituent, or anacid anhydride substituent, said substituent being attached to a ringcarbon atom of the aromatic substrate such that the reaction results inan intramolecular acylation reaction to form a fused ring.
 44. A processaccording to claim 31 wherein the acylating agent is selected from: a C₄to C₁₀ cyclic aliphatic acid halide, a C₂ to C₂₀ linear or branchedaliphatic acid halide or a C₇ to C₂₀ aromatic acid halide; a C₂ to C₂₀carboxylic acid; and a C₄ to C₂₀ acid anhydride; or wherein theacylating agent is a C₃ to C₅ linear aliphatic acid halide substituentor a C₃ to C₅ carboxylic acid substituent, said substituent beingattached to a ring carbon atom of the aromatic substrate such that thereaction is an intramolecular acylation reaction to form a fused ring.45. A process according to claim 31 wherein the acylating agent is aC₂to C₂₀ linear or branched aliphatic acid halide; or a C₃to C₅ linearaliphatic acid halide substituent said substituent being attached to aring carbon atom of the aromatic substrate such that the reaction is anintramolecular acylation to form a fused ring.
 46. A process accordingto claim 43 wherein the acid halide or acid halide substituent is anacid chloride or acid bromide.
 47. A process according to claim 31wherein the acylating agent is selected from acetic anhydride, propanoicanhydride, isobutyric anhydride, acetyl chloride, propanoyl chloride andbutanoyl chloride.
 48. A process according to claim 31 for theFriedel-Crafts acylation of an aromatic substrate with an acylationagent to form a ketone, wherein a system of indium (III) chloride and a1, 3 dialkylated imidazolium chloride or other organic anionic speciesis used.
 49. (canceled)
 50. A process according to claim 31 wherein thealkylation or acylation product is removed from the reaction mixture bya simple extraction of the catalyst system from the reaction mixturewith water.
 51. A process according to claim 31 wherein the indium basedcatalyst system is regenerated by subsequent removal of water from theaqueous wash.
 52. A process according to claim 31 wherein the startingmaterials for the reaction include one or more of the following:toluene, anisole, benzoic anhydride, benzoyl chloride, acetic anhydrideand acetyl chloride.
 53. An acylation process as claimed in claim 29wherein the ionic liquid is an imidazolium chloride selected fromethylmethylimidazolium chloride or butylmethylimidazolium chloride. 54.(canceled)
 55. A process according to claim 31 wherein the reactionproduct is liberated from the solvent solution by washing with hot wateror with an aqueous sodium hydroxide solution.
 56. (canceled)
 57. Use ofa system of indium (III) chloride and a 1,3-dialkylated imidazoliumchloride or other organic cationic species in a Friedel-Crafts acylationreaction.